This invention is directed at a composition for the controlled release of doxorubicin.
Doxorubicin is a commonly used antineoplastic drug. Commonly responsive tumors include acute leukemia, Hodgkin""s disease, other lymphoinas, breast and lung cancer. Doxorubicin has been reported to give a high response rate in the treatment of advanced breast cancer and to give favorable results for the treatment of gastric carcinoma (a tumor for which only four drugs are known to be active). However, doxorubicin has a narrow therapeutic index and causes cardiac toxicity at a cumulative dose of 450 to 550 mg/m2. The usual dosage is 40-75 mg/m2 rapidly intravenous or 30 mg/m2 for three days by continuous IV. Alternative methods of administration have been sought which accommodate the narrow therapeutic index and cumulative dose toxicity. In particular, a controlled release form of doxorubicin has been sought, and glutaraldehyde treated erythrocytes and glutaraldehyde treated albumin have been suggested as carriers for this purpose. However, the glutaraldehyde can react with the doxorubicin causing the doxorubicin to become less active and is potentially toxic, and heat is used in glutaraldehyde treatment of albumin which can inactivate doxorubicin. Accordingly, a carrier for controlled release of doxorubicin has been sought where no chemical cross-linker is necessary and where beat is not involved in the preparation of the carrier.
The invention herein provides a composition for the controlled release of doxorubicin where the carrier is a dextran-methacrylate biodegradable hydrogel and where no chemical cross-linker or heat are necessary for the preparation of the carrier. The composition for the controlled release of doxorubicin comprises doxorubicin physically entrapped in a dextran-methacrylate biodegradable hydrogel. The composition is formed, for example, by photocrosslinking dextran methacrylate monoester in solution in a medium containing doxorubicin and drying, the dextran methacrylate monoester having an average degree of substitution of each xcex1-D-glucopyranosyl of dextran by methacrylic acid ranging from 0.05 to 0.75 and a weight average molecular weight ranging from 40,000 to 80,000 on a dextran basis, e.g., 50,000 to 75,000 on a dextran basis, said medium being buffered to a pH ranging from 2 to 8, the weight ratio of doxorubicin to dextran methacrylate monoester ranging from 1:200 to 1:2000, e.g., from 1:500 to 1:1500.
In one subset of the invention, the dextran methacrylate monoester which is photocrosslinked has an average degree of substitution ranging from 0.05 to 0.15.
In another subset of the invention, the dextran methacrylate monoester which is photocrosslinked has an average degree of substitution ranging from 0.15 to 0.40.
In still another subset of the invention, the dextran methacrylate monoester which is photocrosslinked has an average degree of substitution ranging from 0.40 to 0.75.
The term xe2x80x9cphysically entrappedxe2x80x9d is used herein to mean physically impregnated, i.e., the drug is within the hydrogel network but there has been no chemical reaction between the drug and the hydrogel network.
The term xe2x80x9chydrogelxe2x80x9d is used herein to mean a polymeric material which exhibits the ability to swell in water and to retain a significant portion of water within its structure without dissolution.
The term xe2x80x9cbiodegradable hydrogelxe2x80x9d is used herein mean hydrogel formed by cross-linking a polymer which is degraded by water and/or by enzymes found in the body.
The term xe2x80x9cphotocrosslinkingxe2x80x9d is used herein to mean causing vinyl bonds in the methacryloyl moieties to break and form cross-links by the application of radiant energy.
The term xe2x80x9cdegree of substitutionxe2x80x9d is used herein to mean the number of hydroxyl groups in a glucose unit of xcex1-D-glucopyranosyl moiety of dextran that form ester group with methacrylic acid. Since each said glucose unit contains three hydroxyl groups, the maximum degree of substitution is 3.0. The average degree of substitution connotes the average degree of substitution based on all the glucose units in the molecules of dextran methacrylate monoester.
The term xe2x80x9con a dextran basisxe2x80x9d is used herein to mean that the weight average molecular weight referred to is that of the dextran starting material for preparing the dextran methacrylate monoester which provides the dextran moiety of the dextran methacrylate monoester. The weight average molecular weights referred to herein are those determined on dextran by light scattering or gel permeation chromatography. In the working example herein, the dextran used to prepare the dextran methacrylate monoester was obtained from Sigma Chemicals, and had a weight average molecular weight of 70,000 determined by gel permeation chromatography; therefore, the dextran methacrylate monoester used in the working example herein had a weight average molecular weight of 70,000 on a dextran basis, determined by gel permeation chromatography.